JP2022507837A - Radiation protection nanoparticles - Google Patents
Radiation protection nanoparticles Download PDFInfo
- Publication number
- JP2022507837A JP2022507837A JP2021528315A JP2021528315A JP2022507837A JP 2022507837 A JP2022507837 A JP 2022507837A JP 2021528315 A JP2021528315 A JP 2021528315A JP 2021528315 A JP2021528315 A JP 2021528315A JP 2022507837 A JP2022507837 A JP 2022507837A
- Authority
- JP
- Japan
- Prior art keywords
- nanoparticles
- cerium
- manganese oxide
- radiation
- oxide nanoparticles
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000002105 nanoparticle Substances 0.000 title claims abstract description 239
- 230000005855 radiation Effects 0.000 title claims description 43
- 229910044991 metal oxide Inorganic materials 0.000 claims abstract description 60
- 150000004706 metal oxides Chemical class 0.000 claims abstract description 59
- CETPSERCERDGAM-UHFFFAOYSA-N ceric oxide Chemical compound O=[Ce]=O CETPSERCERDGAM-UHFFFAOYSA-N 0.000 claims description 38
- 229910000422 cerium(IV) oxide Inorganic materials 0.000 claims description 38
- AMWRITDGCCNYAT-UHFFFAOYSA-L hydroxy(oxo)manganese;manganese Chemical compound [Mn].O[Mn]=O.O[Mn]=O AMWRITDGCCNYAT-UHFFFAOYSA-L 0.000 claims description 38
- 229910052760 oxygen Inorganic materials 0.000 claims description 23
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 22
- 239000001301 oxygen Substances 0.000 claims description 22
- WUKWITHWXAAZEY-UHFFFAOYSA-L calcium difluoride Chemical group [F-].[F-].[Ca+2] WUKWITHWXAAZEY-UHFFFAOYSA-L 0.000 claims description 6
- 229910021645 metal ion Inorganic materials 0.000 claims description 6
- 239000002159 nanocrystal Substances 0.000 claims description 6
- 230000001681 protective effect Effects 0.000 claims description 2
- 238000010586 diagram Methods 0.000 abstract description 5
- LQWKWJWJCDXKLK-UHFFFAOYSA-N cerium(3+) manganese(2+) oxygen(2-) Chemical compound [O--].[Mn++].[Ce+3] LQWKWJWJCDXKLK-UHFFFAOYSA-N 0.000 description 122
- 230000005865 ionizing radiation Effects 0.000 description 80
- 210000004027 cell Anatomy 0.000 description 47
- 239000011572 manganese Substances 0.000 description 40
- 230000006378 damage Effects 0.000 description 17
- 239000003642 reactive oxygen metabolite Substances 0.000 description 17
- 241000699670 Mus sp. Species 0.000 description 16
- 230000000694 effects Effects 0.000 description 13
- 210000000056 organ Anatomy 0.000 description 11
- 210000003079 salivary gland Anatomy 0.000 description 10
- 230000006870 function Effects 0.000 description 9
- 230000009467 reduction Effects 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 8
- 210000003296 saliva Anatomy 0.000 description 8
- 210000000130 stem cell Anatomy 0.000 description 8
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 7
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 7
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical class P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 7
- 210000000192 parasympathetic ganglia Anatomy 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 6
- 210000002798 bone marrow cell Anatomy 0.000 description 6
- 238000004833 X-ray photoelectron spectroscopy Methods 0.000 description 5
- 230000030833 cell death Effects 0.000 description 5
- 201000010536 head and neck cancer Diseases 0.000 description 5
- 208000014829 head and neck neoplasm Diseases 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- 239000002953 phosphate buffered saline Substances 0.000 description 5
- 238000001959 radiotherapy Methods 0.000 description 5
- 230000008929 regeneration Effects 0.000 description 5
- 238000011069 regeneration method Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000002056 X-ray absorption spectroscopy Methods 0.000 description 4
- 230000022534 cell killing Effects 0.000 description 4
- 230000007547 defect Effects 0.000 description 4
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 231100000057 systemic toxicity Toxicity 0.000 description 4
- 210000002105 tongue Anatomy 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 102000004392 Aquaporin 5 Human genes 0.000 description 3
- 108090000976 Aquaporin 5 Proteins 0.000 description 3
- 102000004127 Cytokines Human genes 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 238000001237 Raman spectrum Methods 0.000 description 3
- 238000002441 X-ray diffraction Methods 0.000 description 3
- 208000005946 Xerostomia Diseases 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 206010013781 dry mouth Diseases 0.000 description 3
- 239000000975 dye Substances 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- 239000007850 fluorescent dye Substances 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 230000028993 immune response Effects 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 210000000214 mouth Anatomy 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000002000 scavenging effect Effects 0.000 description 3
- 210000000813 small intestine Anatomy 0.000 description 3
- 210000000952 spleen Anatomy 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- LOGFVTREOLYCPF-KXNHARMFSA-N (2s,3r)-2-[[(2r)-1-[(2s)-2,6-diaminohexanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxybutanoic acid Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H]1CCCN1C(=O)[C@@H](N)CCCCN LOGFVTREOLYCPF-KXNHARMFSA-N 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- QGLWBTPVKHMVHM-KTKRTIGZSA-N (z)-octadec-9-en-1-amine Chemical compound CCCCCCCC\C=C/CCCCCCCCN QGLWBTPVKHMVHM-KTKRTIGZSA-N 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 208000001395 Acute radiation syndrome Diseases 0.000 description 2
- 102000047934 Caspase-3/7 Human genes 0.000 description 2
- 108700037887 Caspase-3/7 Proteins 0.000 description 2
- 229910052684 Cerium Inorganic materials 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 102000003777 Interleukin-1 beta Human genes 0.000 description 2
- 108090000193 Interleukin-1 beta Proteins 0.000 description 2
- 102000003814 Interleukin-10 Human genes 0.000 description 2
- 108090000174 Interleukin-10 Proteins 0.000 description 2
- 102000004889 Interleukin-6 Human genes 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 description 2
- 102100027754 Mast/stem cell growth factor receptor Kit Human genes 0.000 description 2
- 229910018663 Mn O Inorganic materials 0.000 description 2
- 229910003176 Mn-O Inorganic materials 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
- 206010068142 Radiation sickness syndrome Diseases 0.000 description 2
- 238000001069 Raman spectroscopy Methods 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 210000005178 buccal mucosa Anatomy 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 229910000420 cerium oxide Inorganic materials 0.000 description 2
- HSJPMRKMPBAUAU-UHFFFAOYSA-N cerium(3+);trinitrate Chemical compound [Ce+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O HSJPMRKMPBAUAU-UHFFFAOYSA-N 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 210000001198 duodenum Anatomy 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 229940076144 interleukin-10 Drugs 0.000 description 2
- 229940100601 interleukin-6 Drugs 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 230000005923 long-lasting effect Effects 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 230000000394 mitotic effect Effects 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 210000002220 organoid Anatomy 0.000 description 2
- BMMGVYCKOGBVEV-UHFFFAOYSA-N oxo(oxoceriooxy)cerium Chemical compound [Ce]=O.O=[Ce]=O BMMGVYCKOGBVEV-UHFFFAOYSA-N 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000004223 radioprotective effect Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 210000004706 scrotum Anatomy 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 230000009747 swallowing Effects 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- QCHFTSOMWOSFHM-WPRPVWTQSA-N (+)-Pilocarpine Chemical compound C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 description 1
- 208000010470 Ageusia Diseases 0.000 description 1
- 102000017927 CHRM1 Human genes 0.000 description 1
- 102000017925 CHRM3 Human genes 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 108090000397 Caspase 3 Proteins 0.000 description 1
- 102100029855 Caspase-3 Human genes 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 208000003098 Ganglion Cysts Diseases 0.000 description 1
- 101000782981 Homo sapiens Muscarinic acetylcholine receptor M1 Proteins 0.000 description 1
- 101000928919 Homo sapiens Muscarinic acetylcholine receptor M3 Proteins 0.000 description 1
- 101100241084 Homo sapiens NRTN gene Proteins 0.000 description 1
- 229910021380 Manganese Chloride Inorganic materials 0.000 description 1
- 201000002481 Myositis Diseases 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 102100021584 Neurturin Human genes 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- QCHFTSOMWOSFHM-UHFFFAOYSA-N SJ000285536 Natural products C1OC(=O)C(CC)C1CC1=CN=CN1C QCHFTSOMWOSFHM-UHFFFAOYSA-N 0.000 description 1
- 206010039424 Salivary hypersecretion Diseases 0.000 description 1
- 208000005400 Synovial Cyst Diseases 0.000 description 1
- 238000012288 TUNEL assay Methods 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 102100040247 Tumor necrosis factor Human genes 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 238000000026 X-ray photoelectron spectrum Methods 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000006022 acute inflammation Effects 0.000 description 1
- 208000038016 acute inflammation Diseases 0.000 description 1
- 235000019666 ageusia Nutrition 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000009141 biological interaction Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 210000003850 cellular structure Anatomy 0.000 description 1
- GWXLDORMOJMVQZ-UHFFFAOYSA-N cerium Chemical compound [Ce] GWXLDORMOJMVQZ-UHFFFAOYSA-N 0.000 description 1
- YOSLGHBNHHKHST-UHFFFAOYSA-N cerium manganese Chemical compound [Mn].[Mn].[Mn].[Mn].[Mn].[Ce] YOSLGHBNHHKHST-UHFFFAOYSA-N 0.000 description 1
- 230000001055 chewing effect Effects 0.000 description 1
- 208000031513 cyst Diseases 0.000 description 1
- NJDNXYGOVLYJHP-UHFFFAOYSA-L disodium;2-(3-oxido-6-oxoxanthen-9-yl)benzoate Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C1=C2C=CC(=O)C=C2OC2=CC([O-])=CC=C21 NJDNXYGOVLYJHP-UHFFFAOYSA-L 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 210000003989 endothelium vascular Anatomy 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229910021397 glassy carbon Inorganic materials 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical compound [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000010874 in vitro model Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 208000037817 intestinal injury Diseases 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000037041 intracellular level Effects 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 210000001630 jejunum Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000011565 manganese chloride Substances 0.000 description 1
- 229940099607 manganese chloride Drugs 0.000 description 1
- 235000002867 manganese chloride Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000000968 medical method and process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 238000000593 microemulsion method Methods 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 238000007481 next generation sequencing Methods 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 210000003254 palate Anatomy 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 230000004796 pathophysiological change Effects 0.000 description 1
- 230000006320 pegylation Effects 0.000 description 1
- 229960001416 pilocarpine Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 238000003608 radiolysis reaction Methods 0.000 description 1
- 230000001603 reducing effect Effects 0.000 description 1
- 230000006335 response to radiation Effects 0.000 description 1
- 208000026451 salivation Diseases 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000001913 submandibular gland Anatomy 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 239000011800 void material Substances 0.000 description 1
- -1 water Chemical compound 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01F—COMPOUNDS OF THE METALS BERYLLIUM, MAGNESIUM, ALUMINIUM, CALCIUM, STRONTIUM, BARIUM, RADIUM, THORIUM, OR OF THE RARE-EARTH METALS
- C01F17/00—Compounds of rare earth metals
- C01F17/20—Compounds containing only rare earth metals as the metal element
- C01F17/206—Compounds containing only rare earth metals as the metal element oxide or hydroxide being the only anion
- C01F17/224—Oxides or hydroxides of lanthanides
- C01F17/235—Cerium oxides or hydroxides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/244—Lanthanides; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/32—Manganese; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01G—COMPOUNDS CONTAINING METALS NOT COVERED BY SUBCLASSES C01D OR C01F
- C01G45/00—Compounds of manganese
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01G—COMPOUNDS CONTAINING METALS NOT COVERED BY SUBCLASSES C01D OR C01F
- C01G45/00—Compounds of manganese
- C01G45/02—Oxides; Hydroxides
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09C—TREATMENT OF INORGANIC MATERIALS, OTHER THAN FIBROUS FILLERS, TO ENHANCE THEIR PIGMENTING OR FILLING PROPERTIES ; PREPARATION OF CARBON BLACK ; PREPARATION OF INORGANIC MATERIALS WHICH ARE NO SINGLE CHEMICAL COMPOUNDS AND WHICH ARE MAINLY USED AS PIGMENTS OR FILLERS
- C09C1/00—Treatment of specific inorganic materials other than fibrous fillers; Preparation of carbon black
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09C—TREATMENT OF INORGANIC MATERIALS, OTHER THAN FIBROUS FILLERS, TO ENHANCE THEIR PIGMENTING OR FILLING PROPERTIES ; PREPARATION OF CARBON BLACK ; PREPARATION OF INORGANIC MATERIALS WHICH ARE NO SINGLE CHEMICAL COMPOUNDS AND WHICH ARE MAINLY USED AS PIGMENTS OR FILLERS
- C09C3/00—Treatment in general of inorganic materials, other than fibrous fillers, to enhance their pigmenting or filling properties
- C09C3/06—Treatment with inorganic compounds
- C09C3/063—Coating
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
- A61N2005/1092—Details
- A61N2005/1094—Shielding, protecting against radiation
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2002/00—Crystal-structural characteristics
- C01P2002/60—Compounds characterised by their crystallite size
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2002/00—Crystal-structural characteristics
- C01P2002/70—Crystal-structural characteristics defined by measured X-ray, neutron or electron diffraction data
- C01P2002/76—Crystal-structural characteristics defined by measured X-ray, neutron or electron diffraction data by a space-group or by other symmetry indications
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2002/00—Crystal-structural characteristics
- C01P2002/70—Crystal-structural characteristics defined by measured X-ray, neutron or electron diffraction data
- C01P2002/77—Crystal-structural characteristics defined by measured X-ray, neutron or electron diffraction data by unit-cell parameters, atom positions or structure diagrams
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2002/00—Crystal-structural characteristics
- C01P2002/80—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70
- C01P2002/82—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70 by IR- or Raman-data
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2002/00—Crystal-structural characteristics
- C01P2002/80—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70
- C01P2002/85—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70 by XPS, EDX or EDAX data
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2004/00—Particle morphology
- C01P2004/60—Particles characterised by their size
- C01P2004/64—Nanometer sized, i.e. from 1-100 nanometer
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2004/00—Particle morphology
- C01P2004/80—Particles consisting of a mixture of two or more inorganic phases
- C01P2004/82—Particles consisting of a mixture of two or more inorganic phases two phases having the same anion, e.g. both oxidic phases
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2004/00—Particle morphology
- C01P2004/80—Particles consisting of a mixture of two or more inorganic phases
- C01P2004/82—Particles consisting of a mixture of two or more inorganic phases two phases having the same anion, e.g. both oxidic phases
- C01P2004/84—Particles consisting of a mixture of two or more inorganic phases two phases having the same anion, e.g. both oxidic phases one phase coated with the other
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2006/00—Physical properties of inorganic compounds
- C01P2006/90—Other properties not specified above
Abstract
【課題】放射線保護ナノ粒子を提供する。【解決手段】本発明の放射線保護ナノ粒子は第１の金属酸化物ナノ粒子を含む。上記放射線保護ナノ粒子は、前記第１の金属酸化物ナノ粒子の表面に形成された第２の金属酸化物層をさらに含む。上記放射線保護ナノ粒子は、前記第１の金属酸化物ナノ粒子と前記第２の金属酸化物層との間に極性界面を有する。【選択図】図２PROBLEM TO BE SOLVED: To provide radiation-protected nanoparticles. The radiation-protected nanoparticles of the present invention include first metal oxide nanoparticles. The radiation-protected nanoparticles further include a second metal oxide layer formed on the surface of the first metal oxide nanoparticles. The radiation-protected nanoparticles have a polar interface between the first metal oxide nanoparticles and the second metal oxide layer. [Selection diagram] Fig. 2
Description
本発明は、放射線保護ナノ粒子に関する。 The present invention relates to radiation protected nanoparticles.
大容量の電離放射線（ＩＲ）の露出は、様々な医療分野及び産業において発生することができる。医療分野において、癌患者の５０％以上が費用効果と非侵襲性のために放射線治療を受ける。しかし、放射線療法の間に正常組織は、特に腫瘍塊に近い場合に破損される可能性がある。一例は、頭頸部癌（ｈｅａｄ ａｎｄ ｎｅｃｋ ｃａｎｃｅｒ、ＨＮＣ）の放射線療法中に唾液腺が放射線照射を受けると生じる放射線誘発性唾液分泌不全（ｈｙｐｏ－ｓａｌｉｖａｔｉｏｎ）または口腔乾燥症（ｘｅｒｏｓｔｏｍｉａ）である。 Exposure of large volumes of ionizing radiation (IR) can occur in various medical fields and industries. In the medical field, more than 50% of cancer patients receive radiation therapy for cost-effectiveness and non-invasiveness. However, during radiation therapy, normal tissue can be damaged, especially if it is close to a tumor mass. One example is radiation-induced salivation or xerostomia, which occurs when salivary glands are exposed to radiation during radiation therapy for head and neck cancer (HNC).
頭頸部癌は８番目に一般的な癌であり、毎年５５０，０００件の新しい事例が報告され、頭頸部癌患者の５２％が放射線治療を受ける。放射線誘発性の乾式性筋炎は、頭頸部癌の放射線療法における最大の急性および臓器副作用であり、患者の予後と長期の生活の質に大きく影響を与えることができる咀嚼して飲み込むこと、口腔衛生などの主要口腔機能と関連がある。医療分野以外にも、エネルギー需要が増加するに従って産業分野での原子力利用が急速に増加している。 Head and neck cancer is the eighth most common cancer, with 550,000 new cases reported each year, and 52% of head and neck cancer patients receive radiation therapy. Radiation-induced dry myositis is the largest acute and organ side effect in radiation therapy for head and neck cancer and can significantly affect the prognosis and long-term quality of life of patients. Chewing and swallowing, oral hygiene. It is related to major oral functions such as. In addition to the medical field, the use of nuclear energy in the industrial field is rapidly increasing as energy demand increases.
医療過程でのＩＲに対する露出とは異なるが、偶発的な全身放射線照射（ｔｏｔａｌ ｂｏｄｙ ｉｒｒａｄｉａｔｉｏｎ、ＴＢＩ）は造血症候群および胃腸症候群のような深刻な生命を脅かす結果をもたらす。組織がＩＲに露出されたときに、顕微鏡的に活性酸素種は水の放射線分解を介してミリ秒以内に迅速に生成される。このような活性酸素種は、核酸と細胞構成要素と反応して生物学的機能を破壊し、その上に細胞死滅を誘導する。高い有糸分裂速度を有する細胞がＩＲ誘発活性酸素種にさらに脆弱であるため、先祖細胞／幹細胞または再生に関する組織が普通損傷されて、放射線による損傷は不可逆であり再生成がないように作用する。 Unlike exposure to IR in the medical process, accidental total body irradiation (TBI) has serious life-threatening consequences such as hematopoietic and gastrointestinal syndromes. Microscopically, reactive oxygen species are rapidly produced within milliseconds via radiolysis of water when tissue is exposed to IR. Such reactive oxygen species react with nucleic acids and cell components to destroy biological functions and, on top of that, induce cell death. Because cells with high mitotic rates are more vulnerable to IR-induced reactive oxygen species, ancestral cells / stem cells or tissues involved in regeneration are usually damaged, and radiation damage is irreversible and acts to prevent regeneration. ..
上記のような問題点を解決するために、本発明は放射線保護機能に優れた放射線保護ナノ粒子を提供する。 In order to solve the above-mentioned problems, the present invention provides radiation-protected nanoparticles having an excellent radiation-protecting function.
本発明は、生体適合性に優れた放射線保護ナノ粒子を提供する。 The present invention provides radiation-protected nanoparticles with excellent biocompatibility.
本発明の他の目的は以降の詳細な説明および添付図面から明確になるであろう。 Other objects of the invention will become clear from the following detailed description and accompanying drawings.
本発明の一実施例による放射線保護ナノ粒子は、第１の金属酸化物ナノ粒子を含む。 The radiation protected nanoparticles according to one embodiment of the present invention include the first metal oxide nanoparticles.
上記放射線保護ナノ粒子は、前記第１の金属酸化物ナノ粒子の表面に形成された第２の金属酸化物層をさらに含む。 The radiation-protected nanoparticles further include a second metal oxide layer formed on the surface of the first metal oxide nanoparticles.
上記放射線保護ナノ粒子は、前記第１の金属酸化物ナノ粒子と前記第２の金属酸化物層との間に極性界面を有する。前記極性界面は、（前記第１の金属酸化物の金属イオン）－Ｏ－（前記第２の金属酸化物の金属イオン）のぺアリングを含む。 The radiation-protected nanoparticles have a polar interface between the first metal oxide nanoparticles and the second metal oxide layer. The polar interface comprises pairing of (the metal ion of the first metal oxide) -O- (the metal ion of the second metal oxide).
前記第２の金属酸化物層は、前記第１の金属酸化物ナノ粒子の表面でエピタキシャル成長されて形成される。 The second metal oxide layer is formed by epitaxially growing on the surface of the first metal oxide nanoparticles.
前記第２の金属酸化物層により前記第１の金属酸化物ナノ粒子の表面の酸素空隙が増加する。 The second metal oxide layer increases oxygen voids on the surface of the first metal oxide nanoparticles.
前記第２の金属酸化物層はストレーンされて｛３３２｝面を露出させる。 The second metal oxide layer is strained to expose the {332} surface.
前記第１の金属酸化物はセリアを含み、前記第２の金属酸化物はマンガン酸化物を含む The first metal oxide contains ceria and the second metal oxide contains manganese oxide.
前記第１の金属酸化物ナノ粒子は酸素空隙を有する。前記第１の金属酸化物ナノ粒子は蛍石構造のナノ結晶を有する。 The first metal oxide nanoparticles have oxygen voids. The first metal oxide nanoparticles have nanocrystals having a fluorite structure.
本発明の実施例による放射線保護ナノ粒子は、優れた放射線保護能と生体適合性を持つことができる。上記放射線保護ナノ粒子は、活性酸素種の消去能力を増加させながら全身毒性を減らすことができる。また、上記放射線保護ナノ粒子は、長く持続される安定的な活性と低い活性線量を持つことができる。上記放射線保護ナノ粒子は、様々な放射線誘発の損傷を防止するために、局所的および全身的に使用することができる。上記放射線保護ナノ粒子は、毒性がないか又は小さいだけでなく、少量でも組織及び細胞を放射線から直接保護することができて機能の迅速な再生と回復を促進することができる。 The radiation-protected nanoparticles according to the examples of the present invention can have excellent radiation protection ability and biocompatibility. The radiation-protected nanoparticles can reduce systemic toxicity while increasing the ability to scavenge reactive oxygen species. In addition, the radiation-protected nanoparticles can have long-lasting stable activity and low active dose. The radiation-protected nanoparticles can be used locally and systemically to prevent various radiation-induced damage. Not only are the radiation-protected nanoparticles non-toxic or small, but even small amounts can directly protect tissues and cells from radiation and promote rapid regeneration and recovery of function.
以下、実施例を挙げて本発明を詳細に説明する。本発明の目的、特徴、利点は以下の実施例から容易に理解できるであろう。本発明は、ここで説明される実施例に限定されず、他の形態に具体化されることもできる。ここで紹介される実施例は、開示された内容が徹底的で完全なものとなるように、かつ本発明の属する技術分野における通常の知識を有する者に本発明の思想が十分に伝達されるようにするために提供されるものである。よって、以下の実施例により本発明が限定されてはならない。 Hereinafter, the present invention will be described in detail with reference to examples. The object, features and advantages of the present invention can be easily understood from the following examples. The present invention is not limited to the examples described herein, and may be embodied in other embodiments. In the examples presented herein, the ideas of the present invention are fully communicated so that the disclosed contents are thorough and complete, and to a person having ordinary knowledge in the technical field to which the present invention belongs. It is provided to ensure that. Therefore, the present invention should not be limited by the following examples.
本明細書において、第１、第２などの用語が様々な要素（ｅｌｅｍｅｎｔｓ）を記述するために使用されたが、前記要素がこのような用語によって限定されてはならない。この用語は、単に前記要素を相互に区別するために使用されただけである。また、とある要素が他の要素上にあると言及されている場合に、それは、他の要素上に直接形成されること、またはそれらの間に第３の要素が介在することもできることを意味する。 In the present specification, terms such as first and second have been used to describe various elements, but the elements should not be limited by such terms. This term has only been used to distinguish the elements from each other. Also, when one element is mentioned to be on another, it means that it can be formed directly on another element, or a third element can intervene between them. do.
本明細書と添付された図面で使用される用語である＋ＩＲとＩＲ＋は放射線が照射されたことを意味し、－ＩＲとＩＲ－は放射線が照射されないことを意味し、＋ＣＭとＣＭ＋はセリウム－マンガン酸化物ナノ粒子で処理されたこと（例えば、生体に投与されたり注入されたりすること）を意味し、－ＣＭとＣＭ－はセリウム－マンガン酸化物ナノ粒子で処理されないことを意味する。たとえば、＋ＩＲ／＋ＣＭとＩＲ＋ＣＭ＋は放射線が照射されてセリウム－マンガン酸化物ナノ粒子で処理されたグループを示し、＋ＩＲ／－ＣＭとＩＲ＋ＣＭ－は、放射線は照射されたがセリウム－マンガン酸化物ナノ粒子で処理されないグループを示す。 The terms + IR and IR + used in this specification and the accompanying drawings mean that they were exposed to radiation, -IR and IR- mean that they were not exposed to radiation, and + CM and CM + mean cerium-. It means that it has been treated with manganese oxide nanoparticles (eg, administered or injected into a living body), meaning that -CM and CM- have not been treated with cerium-manganese oxide nanoparticles. For example, + IR / + CM and IR + CM + indicate groups that have been exposed to radiation and treated with cerium-manganese oxide nanoparticles, and + IR / -CM and IR + CM- indicate groups that have been irradiated but treated with cerium-manganese oxide nanoparticles. Indicates a group that is not processed by.
本発明の一実施例による放射線保護ナノ粒子は、第１の金属酸化物ナノ粒子を含む。前記第１の金属酸化物ナノ粒子は酸素空隙を有する。 The radiation protected nanoparticles according to one embodiment of the present invention include the first metal oxide nanoparticles. The first metal oxide nanoparticles have oxygen voids.
前記第１の金属酸化物ナノ粒子は蛍石構造のナノ結晶を有する。前記第１の金属酸化物は、例えば、セリア（セリウム酸化物）を含む。 The first metal oxide nanoparticles have nanocrystals having a fluorite structure. The first metal oxide includes, for example, ceria (cerium oxide).
本発明の他の実施例による放射線保護ナノ粒子は、第１の金属酸化物ナノ粒子及び前記第１の金属酸化物ナノ粒子の表面に形成された第２の金属酸化物層を含む。 The radiation-protected nanoparticles according to another embodiment of the present invention include a first metal oxide nanoparticles and a second metal oxide layer formed on the surface of the first metal oxide nanoparticles.
上記放射線保護ナノ粒子は、前記第１の金属酸化物ナノ粒子と前記第２の金属酸化物層との間に極性界面を有する。前記極性界面は、（前記第１の金属酸化物の金属イオン）－Ｏ－（前記第２の金属酸化物の金属イオン）のぺアリングを含む。例えば、前記第１の金属酸化物はセリアを含み、前記第２の金属酸化物はマンガン酸化物を含み、前記極性界面はＣｅ４＋－Ｏ－Ｍｎ２＋ペアリングを含む。すなわち、上記放射線保護ナノ粒子は、セリア（ＣｅＯ２）ナノ粒子、前記セリアナノ粒子の表面に形成されたマンガン酸化物（Ｍｎ３Ｏ４）層、および前記セリアナノ粒子と前記マンガン酸化物層との間のヘテロ界面でのＣｅ４＋－Ｏ－Ｍｎ２＋ペアリングを含む。 The radiation-protected nanoparticles have a polar interface between the first metal oxide nanoparticles and the second metal oxide layer. The polar interface comprises pairing of (the metal ion of the first metal oxide) -O- (the metal ion of the second metal oxide). For example, the first metal oxide contains ceria, the second metal oxide contains manganese oxide, and the polar interface comprises Ce 4+ -O-Mn 2+ pairing. That is, the radiation-protected nanoparticles are ceria (CeO 2 ) nanoparticles, a manganese oxide (Mn 3 O 4 ) layer formed on the surface of the ceria nanoparticles, and between the ceria nanoparticles and the manganese oxide layer. Includes Ce 4+ -O-Mn 2+ pairing at the hetero interface of.
前記第１の金属酸化物ナノ粒子は酸素空隙を有する。 The first metal oxide nanoparticles have oxygen voids.
前記第１の金属酸化物ナノ粒子は蛍石構造のナノ結晶を有する。前記第２の金属酸化物層は、前記第１の金属酸化物ナノ粒子の表面でエピタキシャル成長されて形成される。前記第２の金属酸化物層により前記第１の金属酸化物ナノ粒子の表面の酸素空隙が増加する。前記第２の金属酸化物層はストレーンされて｛３３２｝面を露出させる。 The first metal oxide nanoparticles have nanocrystals having a fluorite structure. The second metal oxide layer is formed by epitaxially growing on the surface of the first metal oxide nanoparticles. The second metal oxide layer increases oxygen voids on the surface of the first metal oxide nanoparticles. The second metal oxide layer is strained to expose the {332} surface.
前記放射線保護ナノ粒子は、可視光線ラマンスペクトルでＦ２ｇピークとＡ１ｇピークを有する。前記放射線保護ナノ粒子の表面酸素還元ピークは、Ｈ２ＴＰＲ（ｔｅｍｐｅｒａｔｕｒｅ－ｐｒｏｇｒａｍｍｅｄ ｒｅｄｕｃｔｉｏｎ、ＴＰＲ）において、前記第１の金属酸化物及び前記第２の金属酸化物の表面酸素還元ピークの温度よりもさらに低い温度で発生する。 The radiation-protected nanoparticles have an F 2 g peak and an A 1 g peak in a visible light Raman spectrum. The surface oxygen reduction peak of the radiation-protected nanoparticles is higher than the temperature of the surface oxygen reduction peaks of the first metal oxide and the second metal oxide in H2 TPR (temperature-projected reduction, TPR). Occurs at low temperatures.
図１は本発明の一実施例による放射線保護ナノ粒子を示す。 FIG. 1 shows radiation-protected nanoparticles according to an embodiment of the present invention.
図１を参照すると、上記放射線保護ナノ粒子はセリアナノ粒子含む。前記セリアナノ粒子は酸素空隙を有することができる。前記セリアナノ粒子は蛍石構造のナノ結晶を有しており、（１１１）面の格子間隔は３．１４Åである。 Referring to FIG. 1, the radiation protected nanoparticles include ceria nanoparticles. The ceria nanoparticles can have oxygen voids. The ceria nanoparticles have nanocrystals with a fluorite structure, and the lattice spacing of the (111) plane is 3.14 Å.
前記セリアナノ粒子は、以下の方法で形成することができる。 The ceria nanoparticles can be formed by the following method.
１－ドデカノール（ｄｏｄｅｃａｎｏｌ）１５ｍＬ中硝酸セリウム（III）０．４３ｇとオレイルアミン２．７ｇとオレイン酸０．０３ｇとの混合溶液を空気中で１２０ ℃に加熱する。前記混合溶液が黄色に変わるまで数分間熟成させる。加熱過程で約９０℃の蒸留水０．３ｍＬを添加する。反応後に過量のアセトン、エタノールおよびアセトニトリルを添加してセリアナノ粒子を精製する。前記セリアナノ粒子は遠心分離によって分離されて収集される。このように、マイクロエマルジョン方法を用いて、１－ドデカノール溶液で｛１００｝と｛１１１｝面（ｐｌａｎｅ）によって主に囲まれた４ｎｍサイズの末端が切られた８面体セリアナノ粒子を形成することができる。 A mixed solution of 0.43 g of cerium nitrate (III), 2.7 g of oleylamine and 0.03 g of oleic acid in 15 mL of 1-dodecanol is heated to 120 ° C. in air. Aged for a few minutes until the mixed solution turns yellow. In the heating process, add 0.3 mL of distilled water at about 90 ° C. After the reaction, excess acetone, ethanol and acetonitrile are added to purify the ceria nanoparticles. The ceria nanoparticles are separated and collected by centrifugation. Thus, the microemulsion method can be used to form 4 nm sized, truncated octahedral ceria nanoparticles, predominantly surrounded by {100} and {111} planes (planes) in 1-dodecanol solution. can.
図２は本発明の他の実施例による放射線保護ナノ粒子を示す。 FIG. 2 shows radiation-protected nanoparticles according to another embodiment of the present invention.
図２を参照すると、上記放射線保護ナノ粒子はセリウム－マンガン酸化物ナノ粒子を含む。前記セリウム－マンガン酸化物ナノ粒子は、セリウム酸化物（セリア）とマンガン酸化物を含む。前記セリウム－マンガン酸化物ナノ粒子は、セリアナノ粒子及び前記セリアナノ粒子の表面に形成されたマンガン酸化物層を含む。 Referring to FIG. 2, the radiation protected nanoparticles include cerium-manganese oxide nanoparticles. The cerium-manganese oxide nanoparticles include cerium oxide (ceria) and manganese oxide. The cerium-manganese oxide nanoparticles include ceria nanoparticles and a manganese oxide layer formed on the surface of the ceria nanoparticles.
前記セリウム－マンガン酸化物ナノ粒子は、前記セリアナノ粒子と前記マンガン酸化物層との間に極性界面を持つ。前記極性界面はＣｅ４＋－Ｏ－Ｍｎ２＋ペアリングを含む。すなわち、前記セリウム－マンガン酸化物ナノ粒子は、セリア（ＣｅＯ２）ナノ粒子、前記セリアナノ粒子の表面に形成されたマンガン酸化物（Ｍｎ３Ｏ４）層、および前記セリアナノ粒子と前記マンガン酸化物層との間のヘテロ界面でのＣｅ４＋－Ｏ－Ｍｎ２＋ペアリングを含むことができる。 The cerium-manganese oxide nanoparticles have a polar interface between the ceria nanoparticles and the manganese oxide layer. The polar interface comprises Ce 4+ -O-Mn 2+ pairing. That is, the cerium-manganese oxide nanoparticles are ceria (CeO 2 ) nanoparticles, a manganese oxide (Mn 3 O 4 ) layer formed on the surface of the ceria nanoparticles, and the ceria nanoparticles and the manganese oxide layer. Ce 4+ -O-Mn 2+ pairing at the hetero interface between and can be included.
前記セリアナノ粒子は酸素空隙を持つ。前記セリアナノ粒子は蛍石構造のナノ結晶を持つ。前記マンガン酸化物層は、前記セリアナノ粒子の表面でエピタキシャル成長されて形成されることができる。前記マンガン酸化物層によって前記セリアナノ粒子の表面の酸素空隙が増加することができる。前記マンガン酸化物層は、ストレーンされて｛３３２｝面を露出させることができる。前記セリウム－マンガン酸化物ナノ粒子は、ストレーンによって誘導された高指数（ｈｉｇｈ ｉｎｄｅｘ）のＭｎ３Ｏ４｛３３２｝ファセット（ｆａｃｅｔｓ）を有する。図２のＨＡＡＤＦ－ＳＴＥＭ（Ｈｉｇｈ－ａｎｇｌｅ ａｎｎｕｌａｒ ｄａｒｋ－ｆｉｅｌｄ ｓｃａｎｎｉｎｇ ｔｒａｎｓｍｉｓｓｉｏｎ ｅｌｅｃｔｒｏｎ ｍｉｃｒｏｓｃｏｐｙ）イメージは、マンガン酸化物の不均一沈着後にもセリアナノ粒子のモルホロジー（ｍｏｒｐｈｏｌｏｇｙ）がよく保存されることを見せる。 The ceria nanoparticles have oxygen voids. The ceria nanoparticles have nanocrystals with a fluorite structure. The manganese oxide layer can be formed by epitaxially growing on the surface of the ceria nanoparticles. The manganese oxide layer can increase the oxygen voids on the surface of the ceria nanoparticles. The manganese oxide layer can be strained to expose the {332} surface. The cerium-manganese oxide nanoparticles have a strain-induced high index Mn 3 O 4 {332} facets. The HAADF-STEM (High-angle annular dark-field scanning microscopic) image of FIG. 2 shows that the morphology of ceria nanoparticles is well preserved even after heterogeneous deposition of manganese oxide.
前記セリウム－マンガン酸化物ナノ粒子は、以下のような方法で形成することができる。 The cerium-manganese oxide nanoparticles can be formed by the following method.
セリアナノ粒子０．０９ｇ、オレイルアミン１．３４ｇ、オレイン酸０．１４ｇ、塩酸０．２６ｍＬ、及びキシレン１５ｍＬの混合溶液を９０℃に加熱する。０．３８Ｍ塩化マンガン（ＩＩ）０．８ｍＬの水溶液を加熱された前記混合溶液に迅速に注入する。前記混合溶液を２時間熟成させた後、セリウム－マンガン酸化物ナノ粒子をヘキサンとエタノールで洗浄し、遠心分離によって分離されて収集される。このように、セリアナノ粒子をＭｎ２＋イオンと反応させてヘテロ構造のセリウム－マンガン酸化物ナノ粒子を形成することができる。前記ヘテロ構造のセリウム－マンガン酸化物ナノ粒子はクロロホルムによく分散される。 A mixed solution of 0.09 g of ceria nanoparticles, 1.34 g of oleylamine, 0.14 g of oleic acid, 0.26 mL of hydrochloric acid, and 15 mL of xylene is heated to 90 ° C. A 0.8 mL aqueous solution of 0.38 M manganese chloride (II) is rapidly injected into the heated mixed solution. After aging the mixed solution for 2 hours, the cerium-manganese oxide nanoparticles are washed with hexane and ethanol, separated by centrifugation and collected. In this way, cerium-manganese oxide nanoparticles having a heterostructure can be formed by reacting the ceria nanoparticles with Mn 2+ ions. The heterostructured cerium-manganese oxide nanoparticles are well dispersed in chloroform.
セリア及びヘテロ構造のセリウム－マンガン酸化物ナノ粒子の結晶相はＸＲＤ（Ｘ－ｒａｙ ｄｉｆｆｒａｃｔｉｏｎ）によって特徴づけられることができる。前記セリウム－マンガン酸化物ナノ粒子のＸＲＤパターンはセリアナノ粒子とほぼ同一であり、これはマンガン酸化物が均一沈殿せずにセリアナノ粒子でエピタキシャル成長されたことを意味する。 The crystalline phase of ceria and heterostructured cerium-manganese oxide nanoparticles can be characterized by XRD (X-ray diffraction). The XRD pattern of the cerium-manganese oxide nanoparticles is almost the same as that of the ceria nanoparticles, which means that the manganese oxide was epitaxially grown on the ceria nanoparticles without uniform precipitation.
図３から図１０は、図１及び図２の放射線保護ナノ粒子の特性を説明するための図である。 3 to 10 are diagrams for explaining the characteristics of the radiation-protected nanoparticles of FIGS. 1 and 2.
マンガン酸化物（Ｍｎ３Ｏ４）層は、厚さが約１ｎｍであり、Ｍｎ対Ｃｅのモル比が１５～３０％であるときに３原子層の｛１１２｝面である。ＸＰＳ（Ｘ－ｒａｙ ｐｈｏｔｏｅｌｅｃｔｒｏｎ ｓｐｅｃｔｒｏｓｃｏｐｙ）、ＸＡＳ（Ｘ－ｒａｙ ａｂｓｏｒｐｔｉｏｎ ｓｐｅｃｔｒａ）及びＳＴＥＭを通じて、セリア上のマンガン酸化物の成長メカニズムを分析することができる。４５．８％Ｃｅ３＋を有するセリア（ＣｅＯ２）ナノ粒子は、ＸＰＳによって証明されたように、Ｍｎ２＋との反応後に少し酸化されて４１．３％のＣｅ３＋を有する（図３）。 The manganese oxide (Mn 3 O 4 ) layer is the {112} plane of the triatomic layer when the thickness is about 1 nm and the molar ratio of Mn to Ce is 15-30%. The growth mechanism of manganese oxide on ceria can be analyzed through XPS (X-ray photoelectron spectroscopy), XAS (X-ray absorption spectroscopy) and STEM. Ceria (CeO 2 ) nanoparticles with 45.8% Ce 3+ are slightly oxidized after reaction with Mn 2+ to have 41.3% Ce 3+ , as evidenced by XPS (FIG. 3).
Ｃｅに比べて１５％以下のＭｎがセリアナノ粒子に沈着されたとき、Ｍｎの酸化状態はほとんどＭｎ２＋であり、Ｃｅ４＋－Ｏ－Ｍｎ２＋極性界面を形成する（図４）。しかし、１～３原子層のマンガン酸化物の場合、Ｍｎ２＋とＭｎ３＋の両方が観察される。ＸＰＳ、ＸＡＳデータおよび既知の格子パラメータとＭｎ３Ｏ４の原子配列を結合すると、ヘテロ構造のセリウム－マンガン酸化物ナノ粒子（ＣｅＭｎＮＣ）は、ＣｅＯ２、ヘテロ界面でのＣｅ４＋－Ｏ－Ｍｎ２＋のペアリング、およびＭｎ３Ｏ４で構成される。これは可視光線（５３２ｎｍ）ラマンスペクトル（図５）によって支持される。セリウム－マンガン酸化物ナノ粒子のスペクトルは、ＣｅＯ２（４５２ｃｍ－１）の１次Ｆ２ｇ対称モードとＭｎ３Ｏ４（６４５ｃｍ－１）のＡ１ｇ対称ストレッチングＭｎ－Ｏ結合ピークの両方を示す。ＣｅＯ２とＭｎ３Ｏ４との間のヘテロ界面でのＣｅ－Ｏ結合とＭｎ－Ｏ結合の対称減少により、ピークの拡張が説明されることができる。Ｆ２ｇピークの非対称ピーク拡張とレッドシフトは、活性酸素種を除去するのに不可欠な欠陥数がさらに多いことを示す。 When Mn of 15% or less as compared with Ce is deposited on the ceria nanoparticles, the oxidation state of Mn is almost Mn 2+ , forming a Ce 4+ -O-Mn 2+ polar interface (FIG. 4). However, in the case of manganese oxide with 1 to 3 atomic layers, both Mn 2+ and Mn 3+ are observed. Combining XPS, XAS data and known lattice parameters with the atomic arrangement of Mn 3 O 4 , the heterostructured cerium-manganese oxide nanoparticles (CemNNC) are CeO 2 , Ce 4+ -O-Mn 2+ at the hetero interface. Pairing and Mn 3 O 4 . This is supported by the visible light (532 nm) Raman spectrum (FIG. 5). The spectra of cerium-manganese oxide nanoparticles show both the primary F 2g symmetry mode of CeO 2 (452cm -1 ) and the A 1g symmetric stretching Mn-O binding peak of Mn 3 O 4 (645cm -1 ). .. The symmetry reduction of Ce—O and Mn—O bonds at the hetero interface between CeO 2 and Mn 3 O 4 can explain the expansion of the peak. The asymmetric peak expansion and red shift of the F 2g peak indicates that the number of defects essential for removing reactive oxygen species is even higher.
拡張されたＡ１ｇピークは極性界面（Ｃｅ４＋－Ｏ－Ｍｎ２＋）と格子不一致（ｌａｔｔｉｃｅ ｍｉｓｍａｔｃｈ）によって誘導されたＭｎ３Ｏ４層のエピタキシャルストレーンに起因する。Ｍｎ３Ｏ４層のモホロジーはまたエピタキシャルストレーンを支持することができる。ＣｅＯ２（１１１）面とＭｎ３Ｏ４（１１２）面との間の格子不一致は約１．２％に過ぎないので、Ｍｎ３Ｏ４はＣｅＯ２（１１１）面と平行な［１１２］方向に成長することができる。 The expanded A 1 g peak is due to the epitaxial strain of the Mn 3 O 4 layer induced by the polar interface (Ce 4+ -O-Mn 2+ ) and the lattice mismatch. The morphology of the Mn 3 O 4 layer can also support epitaxial strains. Since the lattice mismatch between the CeO 2 (111) plane and the Mn 3 O 4 (112) plane is only about 1.2%, the Mn 3 O 4 is in the [112] direction parallel to the CeO 2 (111) plane. Can grow into.
他の面による大きな格子不一致に起因するストレーンを最小化するために、｛１１２｝面のステップである高指数ファセットのＭｎ３Ｏ４｛３３２｝が露出されることができる（図２）。ＵＶ（３２５ｎｍ）のラマンスペクトルは、ＣｅＯ２ナノ粒子とセリウム－マンガン酸化物ナノ粒子との間の表面欠陥を比較するために使用される（図６）。５９８ｃｍ－１での欠陥誘導（Ｄモード）ピークとＦ２ｇピークの強度比率（ＩＤ／ＩＦ２ｇ）はＭｎ３Ｏ４の蒸着後に増加し、これはＣｅＯ２の表面上の酸素空隙の増加を意味する。 High exponential faceted Mn 3 O 4 {332}, which is a step on the {112} surface, can be exposed to minimize strain due to large lattice mismatches due to other surfaces (FIG. 2). The UV (325 nm) Raman spectrum is used to compare surface defects between CeO2 nanoparticles and cerium - manganese oxide nanoparticles (FIG. 6). The intensity ratio of defect induction ( D mode) peaks to F 2g peaks (ID / IF 2g) at 598 cm -1 increased after deposition of Mn 3 O 4 , which increased oxygen voids on the surface of CeO 2 . means.
豊富な酸素空隙を有するセリウム－マンガン酸化物ナノ粒子は、活性酸素種の消去に高い活性を示し、これはセリウム－マンガン多重金属酸化物ナノ粒子がＣｅＯ２よりもＣｅ３＋の濃度が少し低いにもかかわらず、全体のナノ粒子に対する電荷非偏在化（ｃｈａｒｇｅ ｄｅｌｏｃａｌｉｚａｔｉｏｎ）に起因することができる（化学的に活性であるコロイドセリアナノ粒子においてＣｅ３＋サイトがない）。欠陥酸化物の表面はまたＯ １ｓ ＸＰＳスペクトルによって検出されることができる（図７）。 Cerium-manganese oxide nanoparticles with abundant oxygen voids show high activity in scavenging active oxygen species, which is because cerium-manganese multi-metal oxide nanoparticles have a slightly lower concentration of Ce 3+ than CeO 2 . Nevertheless, it can be due to charge delocalization for the entire nanoparticles (there is no Ce3 + site in chemically active colloidal ceria nanoparticles). The surface of the defective oxide can also be detected by the O1s XPS spectrum (Fig. 7).
約５２９．２ｅＶ、約５３１．５ｅＶ及び５３３．２ｅＶの結合エネルギーは、それぞれ格子酸素（Ｏｌａｔｔ）、表面吸着酸素（Ｏａｄｓ）、および水のように化学吸着された種（Ｏｓｕｒｆ）に割り当てられることができる。５３１～５３２ｅＶの範囲は、表面に親電子性Ｏ２ ２－、Ｏ２－及びＯ－を有する欠陥サイト（ｄｅｆｅｃｔｉｖｅ ｓｉｔｅｓ）を示すので、Ｏａｄｓ／Ｏｌａｔｔ比率から酸素欠陥濃度を推定することができる。 The binding energies of about 529.2 eV, about 531.5 eV and 533.2 eV are allocated to lattice oxygen ( Olatt ), surface oxygen ( Oads ), and chemisorbed species ( Osurf ) such as water, respectively. Can be Since the range of 531 to 532 eV indicates defective sites with electrophilic O 2 2- , O 2- and O - on the surface, the oxygen defect concentration can be estimated from the O ads / O latt ratio. can.
セリウム－マンガン酸化物ナノ粒子（２．１６）の比率がＣｅＯ２（１．０４）よりも高い場合、セリウム－マンガン酸化物ナノ粒子において酸素空隙水準がより高く、ラマン分析で得られた結果と一致する。表面還元性を分析するためにＨ２ＴＰＲ（ｔｅｍｐｅｒａｔｕｒｅ－ｐｒｏｇｒａｍｍｅｄ ｒｅｄｕｃｔｉｏｎ、ＴＰＲ）を測定した（図８）。ＣｅＯ２に対する５０７℃での表面酸素還元ピークと４９８℃でのＭｎ２＋のＭｎ３Ｏ４還元ピークは低温度（３８２℃ ）にシフトし、これはセリウム－マンガン酸化物ナノ粒子に対する表面還元性の向上を示す。 When the ratio of cerium-manganese oxide nanoparticles (2.16) was higher than CeO 2 (1.04), the oxygen void level was higher in the cerium-manganese oxide nanoparticles, and the results obtained by Raman analysis. Match. H 2 TPR (temperature-measured reduction, TPR) was measured to analyze the surface reducibility (FIG. 8). The surface oxygen reduction peak at 507 ° C for CeO 2 and the Mn 3O 4 reduction peak for Mn 2+ at 498 ° C shift to a lower temperature (382 ° C), which is the surface reducing property for cerium-manganese oxide nanoparticles. Show improvement.
ＴＥＭ、ＸＰＳ、ＸＡＳ、ラマンおよびＨ２ＴＰＲの結果によると、ヘテロエピタキシャル工程によって形成されたＣｅ４＋－Ｏ－Ｍｎ２＋極性界面に加えてＭｎ３Ｏ４のいくつの層がセリウム－マンガン酸化物ナノ粒子の高い酸化還元活性表面を形成するのに必要である。 According to the results of TEM, XPS, XAS, Raman and H2 TPR, several layers of Mn 3 O 4 in addition to the Ce 4+ -O-Mn 2 + polar interface formed by the heteroepitaxial step are cerium-manganese oxide nanoparticles. Required to form a high redox active surface of the particles.
図９及び図１０は、Ｈ２Ｏ２と酸素の還元に対するＣｅＯ２、セリウム－マンガン酸化物ナノ粒子及びＭｎ３Ｏ４の触媒活性を示す。図９及び図１０は、それぞれ５．００ｍＭＨ２Ｏ２とＯ２飽和ＰＢＳの存在下にＡｒ飽和ホスフェート緩衝食塩水（ＰＢＳ、０．０１Ｍ）中のガラスカーボン電極（ｇｌａｓｓｙ ｃａｒｂｏｎ ｅｌｅｃｔｒｏｄｅｓ、ＧＣＥ）上に支持された３つのサンプルの循環電圧電流（ＣＶ）を示す。セリウム－マンガン酸化物ナノ粒子は、－０．４Ｖ以下で還元電流が急激に増加して、単一金属ＣｅＯ２及びＭｎ３Ｏ４と比較して改善された触媒活性を示す。 9 and 10 show the catalytic activity of CeO 2 , cerium-manganese oxide nanoparticles and Mn 3 O 4 on the reduction of H 2 O 2 and oxygen. 9 and 10 are on glassy carbon electrodes (GCE) in Ar saturated phosphate buffered saline (PBS, 0.01 M) in the presence of 5.00 mM H 2 O 2 and O 2 saturated PBS, respectively. The circulating voltage current (CV) of the three supported samples is shown. Cerium-manganese oxide nanoparticles show a sharp increase in reduction current below −0.4 V and show improved catalytic activity compared to the single metals CeO 2 and Mn 3 O 4 .
図１１から図１７は、セリウム－マンガン酸化物ナノ粒子の酵素類似活性を説明するための図である。 11 to 17 are diagrams for explaining the enzyme-like activity of cerium-manganese oxide nanoparticles.
セリウム－マンガン酸化物ナノ粒子（ＣｅＭｎ）はＰＥＧ化（ＰＥＧｙｌａｔｉｏｎ）方法を使用して水分散性親水性ナノ粒子に転換される（図１１）。ＰＥＧ化されたセリウム－マンガン酸化物ナノ粒子は、ＰＢＳ（ｐｈｏｓｐｈａｔｅ－ｂｕｆｆｅｒｅｄ ｓａｌｉｎｅ）で９～１５ｎｍの流体力学的直径を示す（図１２）。セリウム－マンガン酸化物ナノ粒子の濃度による細胞生存率を分析すると、セリウム－マンガン酸化物ナノ粒子は生体適合性に優れる（図１３）。 Cerium-manganese oxide nanoparticles (Cemn) are converted to water-dispersible hydrophilic nanoparticles using a PEGylation method (FIG. 11). The PEGylated cerium-manganese oxide nanoparticles show a hydrodynamic diameter of 9-15 nm in PBS (Phosphate-Buffered Saline) (FIG. 12). Analyzing the cell viability based on the concentration of cerium-manganese oxide nanoparticles, cerium-manganese oxide nanoparticles have excellent biocompatibility (FIG. 13).
水性媒体でセリアナノ粒子（ＣｅＯ２）とセリウム－マンガン酸化物ナノ粒子（ＣｅＭｎ）の酵素活性は、ＳＯＤ、ＣＡＴ模倣およびＨＯＲＡＣ（ｈｙｄｒｏｘｙｌ ｒａｄｉｃａｌ ａｎｔｉｏｘｉｄａｎｔ ｃａｐａｃｉｔｙ）分析法を使用して、代表的な活性酸素種、Ｏ２－、Ｈ２Ｏ２、・ＯＨについて証明される（図１４から図１６）。 The enzymatic activity of ceria nanoparticles (CeO 2 ) and cerium-manganese oxide nanoparticles (Cemn) in an aqueous medium is representative of reactive oxygen species using SOD, CAT mimicry and HORAC (hydroxyl radical antioxidant capacity) analysis methods. , O 2- , H 2 O 2 , · OH (FIGS. 14 to 16).
セリウム－マンガン酸化物ナノ粒子（ＣｅＭｎ）は、ＣｅＯ２またはＭｎ３Ｏ４ナノ粒子と比較して３つの代表的な活性酸素種において優れた酵素性能を示す。ＣｅＯ２ナノ粒子に導入されたＭｎイオンがＣｅＯ２の表面での酸素空隙とセリウム－マンガン酸化物ナノ粒子の還元可能性を増加させるからである。その中でも、厚いＭｎ層を有するセリウム－マンガン酸化物ナノ粒子は、薄いＭｎ層よりも高指数ファセットＭｎ｛３３２｝を露出して触媒活性が高いサイトを提供することができるので、優れた酵素性能を示す。 Cerium-manganese oxide nanoparticles (Cemn) exhibit superior enzymatic performance in three representative reactive oxygen species compared to CeO 2 or Mn 3 O 4 nanoparticles. This is because the Mn ions introduced into the CeO 2 nanoparticles increase the oxygen voids on the surface of the CeO 2 and the reducibility of the cerium-manganese oxide nanoparticles. Among them, the cerium-manganese oxide nanoparticles having a thick Mn layer can expose a site having a higher exponential facet Mn {332} than a thin Mn layer to provide a site having high catalytic activity, and thus have excellent enzymatic performance. Is shown.
セリウム－マンガン酸化物ナノ粒子の活性酸素種の消去能を分析するために、蛍光プローブを使用して活性酸素種の細胞内水準を測定する（図１７）。強い蛍光信号がｔＢＨＰだけで処理された細胞において観察され、対照群に比べて活性酸素種の水準が大幅に増加する。しかし、この蛍光信号はｔＢＨＰがＣｅＯ２と一緒に処理される時に大きく抑制され、セリウム－マンガン酸化物ナノ粒子（ＣｅＭｎＮＣ）で処理した時にさらに抑制されてＣｅＯ２ナノ粒子とセリウム－マンガン酸化物ナノ粒子が抗酸化能を示し、セリウム－マンガン酸化物ナノ粒子は細胞水準においてＣｅＯ２ナノ粒子よりも優れた消去能を示す。 In order to analyze the scavenging ability of reactive oxygen species of cerium-manganese oxide nanoparticles, intracellular levels of reactive oxygen species are measured using a fluorescent probe (FIG. 17). Strong fluorescence signals are observed in cells treated with tBHP alone, with significantly increased levels of reactive oxygen species compared to the control group. However, this fluorescence signal is greatly suppressed when tBHP is treated with CeO 2 and further suppressed when treated with cerium-manganese oxide nanoparticles (CemNNC), and the CeO 2 nanoparticles and cerium-manganese oxide nanoparticles. The particles exhibit antioxidant capacity, and the cerium - manganese oxide nanoparticles exhibit superior scavenging capacity to the CeO2 nanoparticles at the cellular level.
図１８から図２４は、放射線誘導損傷からｅＳＭＧに対するセリウム－マンガン酸化物ナノ粒子の保護を説明するための図である。 18 to 24 are diagrams for explaining the protection of cerium-manganese oxide nanoparticles against eSMG from radiation-induced damage.
セリウム－マンガン酸化物ナノ粒子（ＣｅＭｎ）の無血清胚芽顎下腺（ｅｍｂｒｙｏｎｉｃ ｓｕｂｍａｎｄｉｂｕｌａｒ ｇｌａｎｄ、ｅＳＭＧ）の放射線保護能を調査するために、他のモデルに比べて多くの利点を持つ器官生体外培養モデルを使用した。例えば、試験管内モデルは、多くの細胞類型間の相互作用関係を反映することができず、生体内唾液腺ＩＲ損傷モデルは、時間とリソースを多く消費する。しかし、ｅＳＭＧモデルは、先祖細胞（ｐｒｏｇｅｎｉｔｏｒ ｃｅｌｌｓ）、血管内皮（Ｖａｓｃｕｌａｒ ｅｎｄｏｔｈｅｌｉａｌ、ＶＥ）細胞、上皮アシナー／管細胞（ｅｐｉｔｈｅｌｉａｌ ａｃｉｎａｒ／ ｄｕｃｔａｌ ｃｅｌｌｓ）、中間葉細胞（ｍｅｓｅｎｃｈｙｍａｌ ｃｅｌｌｓ）、および副交感神経節細胞（ｐａｒａｓｙｍｐａｔｈｅｔｉｃ ｇａｎｇｌｉｏｎ ｃｅｌｌｓ）を含む様々な細胞類型間の複雑な生物学的相互作用を維持しながら、ＩＲ誘発損傷を調査することに、ただ４８～７２時間がかかる（図１８および図１９）。 An organ in vitro culture model that has many advantages over other models to investigate the radioprotective capacity of the serum-free germ submandibular gland (eSMG) of cerium-manganese oxide nanoparticles (Cemn). It was used. For example, the in vitro model cannot reflect the interactions between many cell types, and the in vivo salivary gland IR injury model consumes a lot of time and resources. However, eSMG models include progenitor cells, Vascural endothelial (VE) cells, epithelial acinar / ductal cells, mesenchymal cells, and accessory cells. It only takes 48-72 hours to investigate IR-induced damage while maintaining complex biological interactions between various cell types, including parasypthetic ganglion cells) (FIGS. 18 and 19).
細胞内の活性酸素種水準はＣｅｌｌＲｏｘ Ｇｒｅｅｎを通じて測定され、上皮つぼみ内の活性酸素種水準はセリウム－マンガン酸化物ナノ粒子投与群において対照群に比べて有意に低かった。これはセリウム－マンガン酸化物ナノ粒子がＩＲによって生成された活性酸素種を効果的に除去するということを示す（図２０）。Ｃ－ｋｉｔ＋唾液腺先祖細胞は、間葉細胞、副交感神経節（ｐａｒａｓｙｍｐａｔｈｅｔｉｃ ｇａｎｇｌｉｏｎ、ＰＳＧ）、血管内皮（ｖａｓｃｕｌａｒ ｅｎｄｏｔｈｅｌｉａｌ、ＶＥ）細胞のようなニッシェ（ｎｉｃｈｅ）や周囲の微細環境と相互作用して、生存と自己再生能力を維持する。 The intracellular reactive oxygen species level was measured through CellRox Green, and the reactive oxygen species level in the epithelial bud was significantly lower in the cerium-manganese oxide nanoparticles-administered group than in the control group. This indicates that the cerium-manganese oxide nanoparticles effectively remove the reactive oxygen species produced by IR (FIG. 20). C-kit + salivary gland progenitor cells survive by interacting with niche and surrounding microenvironments such as mesenchymal cells, parasympathetic ganglia (PSG), vascular endothelium (VE) cells. And maintain self-renewal ability.
唾液腺アシナー細胞が損傷されると、ｃ－ｋｉｔ＋先祖細胞が休眠状態から再度活性化されて新しいアシナー細胞に分化される。したがって、先祖細胞とそのニッシェを放射線損傷から保護することは唾液腺の再生に重要である。 When salivary gland asiner cells are damaged, c-kit + ancestral cells are reactivated from dormant state and differentiated into new asiner cells. Therefore, protecting ancestral cells and their niche from radiation damage is important for salivary gland regeneration.
したがって、免疫組織学的分析を介してセリウム－マンガン酸化物ナノ粒子が上皮細菌管細胞、ＶＥ細胞、ＰＳＧおよびｃ－ｋｉｔ＋先祖細胞に及ぼす放射線防護効果を確認することができる。放射線照射された人間の唾液腺で、アシナー／管細胞の比率は一定に維持されなかった。この現象はマウスｅＳＭＧモデルでも観察された。１３Ｇｙで照射されたｅＳＭＧはアシナー（ＡＱＰ５＋）／管（Ｋ１９＋）細胞比率が有意に減少したが、セリウム－マンガン酸化物ナノ粒子の処理群は改善されたアシナー／管細胞のバランスを示した。 Therefore, it is possible to confirm the radioprotective effect of cerium-manganese oxide nanoparticles on epithelial bacterial tube cells, VE cells, PSG and c-kit + ancestral cells through immunohistological analysis. The asiner / tube cell ratio was not maintained constant in the irradiated human salivary glands. This phenomenon was also observed in the mouse eSMG model. The eSMG irradiated with 13 Gy had a significantly reduced asiner (AQP5 +) / tube (K19 +) cell ratio, while the cerium-manganese oxide nanoparticles treated group showed an improved asiner / tube cell balance.
ＰＳＧ成長と分枝は＋ＩＲ／－ＣＭ群で有意に抑制されたが、＋ＩＲ／＋ＣＭ群はＰＳＧの成長を正常水準に回復させた。全体外植編（ｅｘｐｌａｎｔｓ）の細胞死滅（Ａｐｏｐｔｏｔｉｃ）の速度は、カスパーゼ３／７グロー（Ｃａｓｐａｓｅ３／７ Ｇｌｏ）分析によって測定された。＋ＩＲ／－ＣＭグループは＋ＩＲ／＋ＣＭよりカスパーゼ（ｃａｓｐａｓｅ）３／７活性が有意に増加することを示し、これはセリウム－マンガン酸化物ナノ粒子がＩＲ誘導されたアポトーシス（ａｐｏｐｔｏｓｉｓ）を効果的に保護すること示す。
PSG growth and branching were significantly suppressed in the + IR / -CM group, but the + IR / + CM group restored PSG growth to normal levels. The rate of apoptosis of total explants was measured by
各細胞の類型において活性カスパーゼ３‐陽性細胞を計数してアシナー細胞、ＰＳＧおよびｃ－ｋｉｔ＋先祖細胞の細胞死滅速度を測定し、３つの類型の細胞の全部において、＋ＩＲ／＋ＣＭグループは＋ＩＲ／－ＣＭグループに比べて細胞死滅速度が有意に低い結果がでた。＋ＩＲ／－ＣＭグループにおいて、ｃ－ｋｉｔ＋先祖細胞の数は著しく減少したが、ｃ－ｋｉｔ＋細胞は＋ＩＲ／＋ＣＭ群でよく保存された。 In each cell type, active caspase 3-positive cells were counted to measure the cell killing rate of asiner cells, PSG and c-kit + progenitor cells, and in all three types of cells, the + IR / + CM group was + IR /-. The results showed that the cell death rate was significantly lower than that of the CM group. In the + IR / -CM group, the number of c-kit + ancestral cells was significantly reduced, but the c-kit + cells were well conserved in the + IR / + CM group.
＋ＩＲ／＋ＣＭグループで生存したｃ－ｋｉｔ＋先祖細胞は後でＡＱＰ５＋アシナー細胞に成功的に分化されたが、＋ＩＲ／－ＣＭグループは分化されたアシナー細胞の数を大幅に減少させた（図２１）。 The c-kit + ancestral cells that survived in the + IR / + CM group were later successfully differentiated into AQP5 + Acinar cells, whereas the + IR / -CM group significantly reduced the number of differentiated Acinar cells (FIG. 21). ..
アシナー細胞（ＡＱＰ５、ＣＨＲＭ１、ＣＨＲＭ３）、ＰＳＧ（ＴＵＪ１、ＮＲＴＮ）およびｃ－ｋｉｔ＋先祖細胞（Ｃ－ｋｉｔ）に対するｍＲＮＡ発現水準によってセリウム－マンガン酸化物ナノ粒子の保護効能が定量的に確認された（図２２から図２４）。 The protective efficacy of cerium-manganese oxide nanoparticles was quantitatively confirmed by the mRNA expression level against acinar cells (AQP5, CHRM1, CHRM3), PSG (TUJ1, NRTN) and c-kit + ancestral cells (C-kit) ( 22 to 24).
ＣｅＭｎで処理したｅＳＭＧグループのすべてのマーカーの発現水準は、未処理グループの数値よりも高く、これは免疫蛍光データと類似する。このような結果は、セリウム－マンガン酸化物ナノ粒子が先祖細胞とその周辺構造に対する全体的な放射線保護を提供して前駆細胞が生存し増殖して、機能性アシナー細胞に分化するように助けることを示す。 The expression levels of all markers in the CeMn-treated eSMG group were higher than those in the untreated group, which is similar to immunofluorescence data. These results provide cerium-manganese oxide nanoparticles with overall radiation protection for progenitor cells and their surrounding structures to help progenitor cells survive and proliferate and differentiate into functional asiner cells. Is shown.
ＩＲ後発生する生物学的事件の全体的な悪循環を調査するために、各グループ（グループ当たり１０個のｅＳＭＧから抽出したｍＲＮＡ）の全体的な遺伝子発現水準を、次世代シーケンシングを介して比較した。ＩＲによる活性酸素種の増加は、免疫反応、炎症および細胞死滅を誘導することができる。死んだ細胞の細胞破片は炎症を増加させ、活性酸素種水準はより多くの細胞死滅を誘導することができる。ＩＲは、活性酸素種、炎症反応、免疫反応および細胞死滅に関する様々な遺伝子の急激な増加を誘発したが、セリウム－マンガン酸化物ナノ粒子の処理は、そのような遺伝子の発現水準を緩和させた。ｅＳＭＧ有機体モデルには循環する免疫細胞がないが、部分的にはＩＲによって誘発された急性炎症および免疫反応を反映し、放射線誘発悪循環に関する生物学的過程もセリウム－マンガン酸化物ナノ粒子によって成功的に遮断された。 To investigate the overall vicious circle of biological events that occur after IR, the overall gene expression levels of each group (mRNA extracted from 10 eSMGs per group) are compared via next-generation sequencing. did. Increased reactive oxygen species by IR can induce immune response, inflammation and cell death. Cell debris of dead cells increases inflammation, and reactive oxygen species levels can induce more cell death. IR induced a rapid increase in various genes for reactive oxygen species, inflammatory response, immune response and cell killing, but treatment with cerium-manganese oxide nanoparticles mitigated the expression level of such genes. .. The eSMG organism model lacks circulating immune cells, but partially reflects IR-induced acute inflammation and immune responses, and biological processes for radiation-induced vicious circles have also been successful with cerium-manganese oxide nanoparticles. Was blocked.
図２５から図３５は、生体内に局所的に照射されたＩＲに対するセリウム－マンガン酸化物ナノ粒子の保護を説明するための図であり、図３６から図４９は、生体内に全体的に照射されたＩＲに対するセリウム－マンガン酸化物ナノ粒子の保護を説明するための図である。 25 to 35 are diagrams for explaining the protection of cerium-manganese oxide nanoparticles against IR locally irradiated in the living body, and FIGS. 36 to 49 show the whole living body being irradiated. It is a figure for demonstrating the protection of the cerium-manganese oxide nanoparticles against the IR.
体内でＳＭＧの構造と機能を保護するセリウム－マンガン酸化物ナノ粒子（ＣｅＭｎ）の能力とＩＲで誘発された口腔乾燥症（Ｘｅｒｏｓｔｏｍｉａ）に対する口腔および全身健康をテストした。セリウム－マンガン酸化物ナノ粒子は、ＩＲ前に各管を介してＩＣＲマウスの二つのＳＭＧに注入された。ＳＭＧの位置を視覚的に確認し、４日間に一日５Ｇｙの分量でＸ線の照射を行った（図２５）。 The ability of cerium-manganese oxide nanoparticles (Cemn) to protect the structure and function of SMGs in the body and oral and general health against IR-induced xerostomia were tested. Cerium-manganese oxide nanoparticles were injected into two SMGs of ICR mice via each tube prior to IR. The position of the SMG was visually confirmed, and X-ray irradiation was performed in an amount of 5 Gy per day for 4 days (FIG. 25).
９０日後、マウスは唾液腺機能検査と組織学的分析を受けた。唾液腺機能検査は、ピロカルピン（ｐｉｌｏｃａｒｐｉｎｅ）で刺激したマウスから全体唾液を収集して行われた。ＩＲ後の平均唾液流速は３．５μｌ／ｍｉｎから１．２μｌ／ｍｉｎに減少したが、セリウム－マンガン酸化物ナノ粒子の投与群では、唾液流速が２．５μｌ／ｍｉｎに有意に増加した（図２６）。 After 90 days, the mice underwent salivary gland function testing and histological analysis. The salivary gland function test was performed by collecting whole saliva from mice stimulated with pilocarpine. The average saliva flow velocity after IR decreased from 3.5 μl / min to 1.2 μl / min, but the saliva flow velocity increased significantly to 2.5 μl / min in the cerium-manganese oxide nanoparticles administration group (Fig.). 26).
唾液が舌や頬側粘膜のような口腔組織を完全に包み込むことが重要であるために、生成された唾液が覆う口腔の面積をナトリウムフルオレセインの紙で測定した（図２７）。＋ＩＲ／－ＣＭグループの口腔内でほとんど蛍光染料が観察されなかったが、＋ＩＲ／＋ＣＭグループでは、舌、口蓋、および頬側粘膜の腹部と背中側から蛍光染料が発見された。 Since it is important that saliva completely envelops oral tissues such as the tongue and buccal mucosa, the area of the oral cavity covered by the saliva produced was measured with sodium fluorescein paper (Fig. 27). Little fluorescent dye was observed in the oral cavity of the + IR / -CM group, whereas in the + IR / + CM group, fluorescent dye was found in the abdomen and back of the tongue, palate, and buccal mucosa.
除去された紙に残っているフルオレセイン染料の量は、分光光度計（ｓｐｅｃｔｒｏｐｈｏｔｏｍｅｔｅｒ）で確認した。約２０％の染料が－ＩＲ／－ＣＭと＋ＩＲ／＋ＣＭグループで唾液によって洗い流されたが、＋ＩＲ／－ＣＭグループでほぼ染料が拡散されなかった（図２８）。 The amount of fluorescein dye remaining on the removed paper was confirmed with a spectrophotometer. About 20% of the dye was washed away by saliva in the -IR / -CM and + IR / + CM groups, but almost no dye was diffused in the + IR / -CM group (FIG. 28).
ＩＲによって誘導されたＳＭＧの組織病理学的変化を調査した（図２９）。＋ＩＲ／－ＣＭグループで白血球浸潤および組織線維化のかなりの増加が観察された。しかし、＋ＩＲ／＋ＣＭグループは、－ＩＲ／－ＣＭグループに比べて白血球浸潤や繊維性の変化に有意な差を示さなかった。 The histopathological changes in SMG induced by IR were investigated (Fig. 29). A significant increase in leukocyte infiltration and tissue fibrosis was observed in the + IR / -CM group. However, the + IR / + CM group showed no significant difference in leukocyte infiltration or fibrous changes compared to the -IR / -CM group.
分泌アシナー細胞（ｓｅｃｒｅｔｏｒｙ ａｃｉｎａｒ ｃｅｌｌｓ）をＰＡＳ染色で視覚化した（図３０）。アシナー細胞は＋ＩＲ／－ＣＭグループでほぼ観察されなかったが、＋ＩＲ／＋ＣＭでアシナー細胞数が有意に増加した。アシナー／管細胞の面積を定量化し、ｅＳＭＧ ＩＲモデルで観察したように、＋ＩＲ／－ＣＭグループは顕著に減少されたアシナー／管比（ａｃｉｎａｒ／ｄｕｃｔａｌ ｒａｔｉｏ）を示した。 Secretory acinar cells were visualized by PAS staining (FIG. 30). Almost no asiner cells were observed in the + IR / -CM group, but the number of asiner cells increased significantly in + IR / + CM. The area of acinar / tube cells was quantified and the + IR / -CM group showed a significantly reduced acinar / ductal ratio as observed in the eSMG IR model.
しかし、損傷されたアシナー／管細胞の比率は＋ＩＲ／＋ＣＭグループで部分的に回復された。ＳＭＧ組織の実際細胞の死滅はタネルアッセイ（ＴＵＮＥＬ ａｓｓａｙ）で検査した。提示されたように、ＣｅＭｎ処理グループでは、ＴＵＮＥＬ＋細胞数が有意に減少した（図３１及び図３２）。放射線誘発性の口腔乾燥症は、口腔組織で炎症を起こし、味を失い、口腔内の微生物を破壊し、嚥下困難を起こして患者が食べ物を食べることを難しくする。 However, the damaged asinar / tube cell ratio was partially restored in the + IR / + CM group. Actual cell death of SMG tissue was examined by TUNEL assay. As presented, the TUNEL + cell count was significantly reduced in the CeMn-treated group (FIGS. 31 and 32). Radiation-induced xerostomia causes inflammation of the oral tissue, loss of taste, destruction of microbes in the oral cavity, and difficulty swallowing, making it difficult for patients to eat food.
局所的ＩＲからＳＭＧに転換した結果、ＩＲ後４週に体重が有意に減少した。これは臨床症状と類似する。しかし、セリウム－マンガン酸化物ナノ粒子処理のマウスは、有意な体重減少を示さなかった（図３３）。ＩＲマウスの舌は鈍い糸乳頭状の突起と厚い角質化された層を示した。しかし、セリウム－マンガン酸化物ナノ粒子処理のグループの舌は、通常の厚さの角質化された層と、通常と鈍い糸乳頭状の突起の共存を示した（図３４）。 As a result of the conversion from local IR to SMG, body weight was significantly reduced 4 weeks after IR. This is similar to clinical symptoms. However, mice treated with cerium-manganese oxide nanoparticles did not show significant weight loss (FIG. 33). The tongue of IR mice showed dull thread papillae-like protrusions and a thick keratinized layer. However, the tongues of the cerium-manganese oxide nanoparticle treatment group showed the coexistence of normal-thick keratinized layers with normal and blunt filamentous papillae-like projections (FIG. 34).
唾液の抗菌活性は唾液において最も重要な機能の一つである。口腔バクテリアサンプルをバッカルスワップ（ｂｕｃｃａｌ ｓｗａｐ）で収集し、コロニー形成分析のために培養した。異常に増加したバクテリアコロニー数が＋ＩＲ／－ＣＭグループで観察されたが、＋ＩＲ／＋ＣＭグループでは部分的に有意に減少した（図３５）。このような結果は、局所的に注入されたセリウム－マンガン酸化物ナノ粒子が唾液腺の構造と機能を保護して、唾液腺ＩＲによって誘発された様々な口腔と全身合併症を予防できるという点を示す。 The antibacterial activity of saliva is one of the most important functions in saliva. Oral bacterial samples were collected on a buccal swap and cultured for colonization analysis. An abnormally increased number of bacterial colonies was observed in the + IR / -CM group, but was partially significantly reduced in the + IR / + CM group (FIG. 35). These results indicate that locally injected cerium-manganese oxide nanoparticles can protect the structure and function of salivary glands and prevent various oral and systemic complications induced by salivary gland IR. ..
マウスにＰＢＳまたは５０ｍｇ／ｋｇのセリウム－マンガン酸化物ナノ粒子を腹腔内に注射し、体重を３日間隔で３０日間測定した。セリウム－マンガン酸化物ナノ粒子の注入グループで、ＰＢＳ注入グループに比べて体重が有意に減少しなかった。３０日後にマウスを犠牲させて組織病理検査のために臓器を収穫した。また、臓、腎臓、脾臓、肝臓、心臓、肺、および膀胱を含む７つの主要な臓器で、セリウム－マンガン酸化物ナノ粒子で処理されたマウスで顕著な病理学的変化は観察されなかった。これはセリウム－マンガン酸化物ナノ粒子が著しい全身毒性を示さないことを示す。次に毒性試験に使用されたセリウム－マンガン酸化物ナノ粒子の濃度の１／１００である０．５５ｍｇ／ｋｇの濃度でセリウム－マンガン酸化物ナノ粒子の全身保護能力を試験した。 Mice were injected intraperitoneally with PBS or 50 mg / kg cerium-manganese oxide nanoparticles and body weight was measured at 3-day intervals for 30 days. The cerium-manganese oxide nanoparticles infused group did not lose significantly weight compared to the PBS infused group. Thirty days later, the mice were sacrificed and the organs were harvested for histopathological examination. In addition, no significant pathological changes were observed in mice treated with cerium-manganese oxide nanoparticles in seven major organs, including the viscera, kidneys, spleen, liver, heart, lungs, and bladder. This indicates that the cerium-manganese oxide nanoparticles do not show significant systemic toxicity. Next, the systemic protection ability of the cerium-manganese oxide nanoparticles was tested at a concentration of 0.55 mg / kg, which is 1/100 of the concentration of the cerium-manganese oxide nanoparticles used in the toxicity test.
マウスは、セリウム－マンガン酸化物ナノ粒子の注入後に１３Ｇｙの全身放射線照射（ＴＢＩ）を受けた（図３６）。どんなマウスも－ＩＲ／－ＣＭと－ＩＲ／＋ＣＭグループで死亡しなかった。これはセリウム－マンガン酸化物ナノ粒子の活性容量が全身毒性を起こさないことを示す。＋ＩＲ／－ＣＭグループでマウスの生存率はＴＢＩ後１２日目に５０％に急激に減少し、ＴＢＩ後１５日目に１５匹のマウスがすべて死亡した。しかし、ＴＢＩ後１５０日目に１０匹のマウスが＋ＩＲ／＋ＣＭグループで生存した（図３７）。
Mice received 13 Gy total body irradiation (TBI) after injection of cerium-manganese oxide nanoparticles (FIG. 36). No mice died in the -IR / -CM and -IR / + CM groups. This indicates that the active capacity of the cerium-manganese oxide nanoparticles does not cause systemic toxicity. In the + IR / -CM group, the survival rate of mice decreased sharply to 50% on the 12th day after TBI, and all 15 mice died on the 15th day after TBI. However, 10 mice survived in the + IR / +
セリウム－マンガン酸化物ナノ粒子の処理グループの生存率の増加に寄与した要因を把握するために、主に急性放射線症候群（Ａｃｕｔｅ Ｒａｄｉａｔｉｏｎ Ｓｙｎｄｒｏｍｅ、ＡＲＳ）によって損傷された器官である血液、骨髄細胞（ＢＭＣ）および小腸の短期および長期の病理生理学的変化を観察した。放射線露出に対する最も深刻な反応は、吐き気や疲労を誘発できる循環系でのサイトカイン（ｃｙｔｏｋｉｎｅ）の上昇であるという点が知られている。 To understand the factors that contributed to the increased viability of the treatment group of cerium-manganese oxide nanoparticles, blood and bone marrow cells (BMC), which are organs damaged mainly by acute radiation syndrome (ARS). ) And short-term and long-term pathophysiological changes in the small intestine were observed. It is known that the most serious response to radiation exposure is an increase in cytokines in the circulatory system that can induce nausea and fatigue.
ＴＢＩ後の６時間後に、インターロイキン－１ベータ（Ｉｎｔｅｒｌｅｕｋｉｎ－１ｂｅｔａ）（ＩＬ－１ｂ）、インターロイキン－６（ＩＬ－６）、インターロイキン－１０（ＩＬ－１０）、及び腫瘍壊死因子－α（ＴＮＦ－ａ）を含む４つの血液サイトカインの血清水準が増加した（図４２）。しかし、セリウム－マンガン酸化物ナノ粒子の処理グループは、セリウム－マンガン酸化物ナノ粒子の未処理グループより４つのサイトカインの増加が有意に少なかった。マウスＢＭＣ細胞死滅速度は、ＴＢＩとＢＭＣ細胞死滅がセリウム－マンガン酸化物ナノ粒子の処理グループで有意に抑制された後に測定された（図３８及び図３９）。 Six hours after TBI, interleukin-1 beta (IL-1b), interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor-α ( The serum levels of four blood cytokines, including TNF-a), were increased (FIG. 42). However, the treated group of cerium-manganese oxide nanoparticles had significantly less increase in four cytokines than the untreated group of cerium-manganese oxide nanoparticles. Mouse BMC cell killing rates were measured after TBI and BMC cell killing were significantly suppressed in the cerium-manganese oxide nanoparticles treatment group (FIGS. 38 and 39).
ＴＢＩ後１日ＢＭＣの総数また分離されて係数された（図４０）。ＢＭＣのほぼ９５％はセリウム－マンガン酸化物ナノ粒子の未処理のグループで除去されたが、ＢＭＣの平均５０％だけがセリウム－マンガン酸化物ナノ粒子の処理グループで除去された。ＴＢＩ１日後の血漿ＭＤＡ数準が測定された。セリウム－マンガン酸化物ナノ粒子の処理グループがセリウム－マンガン酸化物ナノ粒子の未処理のグループよりも血漿内ＭＤＡ濃度を有意に減少させた（図４１）。
The total number of
ＴＢＩ後４日目、小腸、肝臓、腎臓、脾臓、肺などの５器官のＭＤＡ数値を測定した（図４３）。 肝臓を除いて、すべての他の臓器はＴＢＩ後ＭＤＡ水準が有意に増加した。－ＩＲ／－ＣＭグループと比較して、セリウム－マンガン酸化物ナノ粒子の処理グループの小腸、脾臓および肺でＭＤＡ水準の有意な上昇は観察されなかった。 On the 4th day after TBI, MDA values of 5 organs such as small intestine, liver, kidney, spleen, and lung were measured (FIG. 43). All other organs, except the liver, had significantly increased post-TBI MDA levels. No significant increase in MDA levels was observed in the small intestine, spleen and lungs of the cerium-manganese oxide nanoparticles treatment group compared to the -IR / -CM group.
放射線障害を誘発する可能性がある放射線誘発性小腸損傷を調査した（図４４）。ＴＢＩの１週間後に十二指腸を収穫して組織病理学的検査を行った。ＴＢＩによって絨毛がひどく損傷されたが、セリウム－マンガン酸化物ナノ粒子の処理グループは相対的に損傷されない絨毛構造を示し、セリウム－マンガン酸化物ナノ粒子の未処理グループよりもさらに長い絨毛の長さを維持した（図４６及び図４７） 。 Radiation-induced small intestinal injuries that could induce radiation damage were investigated (Fig. 44). One week after TBI, the duodenum was harvested and histopathologically examined. The villi were severely damaged by TBI, but the treated group of cerium-manganese oxide nanoparticles showed a relatively undamaged villous structure, and the villi length was even longer than the untreated group of cerium-manganese oxide nanoparticles. Was maintained (FIGS. 46 and 47).
タネルアッセイとＫｉ－６７染色結果は、またセリウム－マンガン酸化物ナノ粒子がＩＲから絨毛とクリプト細胞を保護し、クリプト細胞で幹細胞と先祖細胞の有糸分裂活性を維持できることを示した（図４５）。 Tanel assay and Ki-67 staining results also showed that cerium-manganese oxide nanoparticles could protect villi and crypto cells from IR and maintain mitotic activity of stem and progenitor cells in crypto cells (FIG. 45). ).
セリウム－マンガン酸化物ナノ粒子の処理グループに対する生存したスクリプト細胞の自己再生能力を確認するために、ＴＢＩ後３０分以内にマウスから陰嚢を分離して体外オルガノイド（ｉｎ ｖｉｔｒｏ ｏｒｇａｎｏｉｄ）培養条件で培養した（図４８）。７日後にセリウム－マンガン酸化物ナノ粒子の未処理グループで分離した胆嚢は腸器官を形成することができなかったが、セリウム－マンガン酸化物ナノ粒子の処理グループは有意に増加された器官形成の効率を示した（図４９）。また、セリウム－マンガン酸化物ナノ粒子の処理グループの腸器官は、中央ルーメン、クリプト構造及び絨毛を含む通常のオルガノイド表現型の特徴を示した。しかし、セリウム－マンガン酸化物ナノ粒子の未処理グループで隔離された陰嚢は７日間球状シストを形成することができなかった。 To confirm the self-renewal ability of surviving script cells to a treatment group of cerium-manganese oxide nanoparticles, the scrotum was isolated from mice within 30 minutes after TBI and cultured under in vitro organoid culture conditions. (Fig. 48). Gallbladder separated in the untreated group of cerium-manganese oxide nanoparticles after 7 days was unable to form intestinal organs, whereas the treated group of cerium-manganese oxide nanoparticles had significantly increased organ formation. The efficiency was shown (Fig. 49). In addition, the intestinal organs of the treatment group of cerium-manganese oxide nanoparticles exhibited features of the normal organoid phenotype, including central lumen, cryptostructure and villi. However, the scrotum isolated in the untreated group of cerium-manganese oxide nanoparticles was unable to form spherical cysts for 7 days.
最後に、ＴＢＩ １５０日後に生存したセリウム－マンガン酸化物ナノ粒子の処理マウスから臓器を収穫して、長期間の損傷評価を行った。生存マウスの十二指腸と空腸の両方が腫瘍形成や病因の兆候を示さなかった。 Finally, organs were harvested from mice treated with cerium-manganese oxide nanoparticles that survived 150 days after TBI and evaluated for long-term damage. Both the duodenum and jejunum of surviving mice showed no signs of tumorigenesis or etiology.
以上、本発明の具体的な実施例について考察した。本発明が属する技術分野における通常の知識を有する者は、本発明が本発明の本質的な特性から逸脱しない範囲で変形した形態で具現できることを理解することができるであろう。したがって、開示された実施例は限定的な観点ではなく、説明的な観点で考慮されるべきである。本発明の範囲は前述した説明ではなく、特許請求の範囲に示されており、それと同等の範囲内にあるすべての差異点は本発明に含まれるものと解釈されるべきである。 The specific examples of the present invention have been considered above. Those who have ordinary knowledge in the technical field to which the present invention belongs will understand that the present invention can be embodied in a modified form within a range that does not deviate from the essential characteristics of the present invention. Therefore, the disclosed examples should be considered from a descriptive point of view, not from a limiting point of view. The scope of the invention is set forth in the claims, not the description described above, and all differences within the equivalent scope should be construed as included in the invention.
本発明の実施例による放射線保護ナノ粒子は、優れた放射線保護能と生体適合性を持つことができる。上記放射線保護ナノ粒子は、活性酸素種の消去能力を増加させながら全身毒性を減らすことができる。また、上記放射線保護ナノ粒子は、長く持続される安定的な活性と低い活性線量を持つことができる。上記放射線保護ナノ粒子は、様々な放射線誘発の損傷を防止するために、局所的および全身的に使用することができる。上記放射線保護ナノ粒子は、毒性がないか又は小さいだけでなく、少量でも組織及び細胞を放射線から直接保護することができて機能の迅速な再生と回復を促進することができる。 The radiation-protected nanoparticles according to the examples of the present invention can have excellent radiation protection ability and biocompatibility. The radiation-protected nanoparticles can reduce systemic toxicity while increasing the ability to scavenge reactive oxygen species. In addition, the radiation-protected nanoparticles can have long-lasting stable activity and low active dose. The radiation-protected nanoparticles can be used locally and systemically to prevent various radiation-induced damage. Not only are the radiation-protected nanoparticles non-toxic or small, but even small amounts can directly protect tissues and cells from radiation and promote rapid regeneration and recovery of function.
Claims (10)
The radiation-protected nanoparticles according to claim 1, wherein the first metal oxide nanoparticles have nanocrystals having a fluorite structure.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2018-0087355 | 2018-07-26 | ||
| KR1020180087355A KR102102535B1 (en) | 2018-07-26 | 2018-07-26 | Nanoparticles for radiation protection |
| PCT/KR2019/009065 WO2020022736A1 (en) | 2018-07-26 | 2019-07-23 | Radiation-protective nanoparticles |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2022507837A true JP2022507837A (en) | 2022-01-18 |
Family
ID=69181861
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2021528315A Pending JP2022507837A (en) | 2018-07-26 | 2019-07-23 | Radiation protection nanoparticles |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US20210322468A1 (en) |
| EP (1) | EP3828137A4 (en) |
| JP (1) | JP2022507837A (en) |
| KR (1) | KR102102535B1 (en) |
| CN (1) | CN112533870A (en) |
| WO (1) | WO2020022736A1 (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008546842A (en) * | 2005-06-27 | 2008-12-25 | エドワード ヴィア バージニア カレッジ オブ オステオパシック メディスン | Anti-inflammatory, radioprotective and life-promoting ability of cerium oxide nanoparticles |
| JP2015521538A (en) * | 2012-06-15 | 2015-07-30 | ビーエーエスエフ コーポレーション | Mixed metal oxide composites for oxygen storage |
| JP2016525994A (en) * | 2013-04-25 | 2016-09-01 | セリオン エンタープライジズ リミテッド ライアビリティ カンパニー | Chelated nanoceria for treating oxidative stress |
| JP2017521499A (en) * | 2014-07-17 | 2017-08-03 | バイオキュリティー ホールディングス インコーポレイテッド | Cancer treatment with radiation, cerium oxide nanoparticles, and chemotherapeutic agents |
| KR101789692B1 (en) * | 2016-06-20 | 2017-10-25 | 서울대학교산학협력단 | Multimetallic oxide nanocrystals and method of manufacturing the same |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2017186220A (en) * | 2016-03-30 | 2017-10-12 | 日本碍子株式会社 | Transition metal oxide-containing cerium dioxide particle |
| CN107673391A (en) * | 2017-11-07 | 2018-02-09 | 西安文理学院 | One kind bundle shape ceria metal oxides and preparation method thereof |
-
2018
- 2018-07-26 KR KR1020180087355A patent/KR102102535B1/en active IP Right Grant
-
2019
- 2019-07-23 CN CN201980049891.0A patent/CN112533870A/en active Pending
- 2019-07-23 WO PCT/KR2019/009065 patent/WO2020022736A1/en active Application Filing
- 2019-07-23 US US17/262,142 patent/US20210322468A1/en active Pending
- 2019-07-23 EP EP19841241.3A patent/EP3828137A4/en not_active Withdrawn
- 2019-07-23 JP JP2021528315A patent/JP2022507837A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008546842A (en) * | 2005-06-27 | 2008-12-25 | エドワード ヴィア バージニア カレッジ オブ オステオパシック メディスン | Anti-inflammatory, radioprotective and life-promoting ability of cerium oxide nanoparticles |
| JP2015521538A (en) * | 2012-06-15 | 2015-07-30 | ビーエーエスエフ コーポレーション | Mixed metal oxide composites for oxygen storage |
| JP2016525994A (en) * | 2013-04-25 | 2016-09-01 | セリオン エンタープライジズ リミテッド ライアビリティ カンパニー | Chelated nanoceria for treating oxidative stress |
| JP2017521499A (en) * | 2014-07-17 | 2017-08-03 | バイオキュリティー ホールディングス インコーポレイテッド | Cancer treatment with radiation, cerium oxide nanoparticles, and chemotherapeutic agents |
| KR101789692B1 (en) * | 2016-06-20 | 2017-10-25 | 서울대학교산학협력단 | Multimetallic oxide nanocrystals and method of manufacturing the same |
Non-Patent Citations (4)
| Title |
|---|
| APPLIED MATERIALS AND INTERFACES, vol. 7, JPN6022005189, 2015, pages 16525 - 16535, ISSN: 0004704489 * |
| CHINESE JOURNAL OF CATALYSIS, vol. 35, JPN6022005191, 2014, pages 1260 - 1266, ISSN: 0004704490 * |
| CRYSTAL GROWTH AND DESIGN, vol. 11, JPN6022005188, 2011, pages 1202 - 1207, ISSN: 0004870848 * |
| THE JOURNAL OF PHYSICAL CHEMISTRY C, vol. 118, JPN6022005193, 2014, pages 30187 - 30196, ISSN: 0004704491 * |
Also Published As
| Publication number | Publication date |
|---|---|
| EP3828137A4 (en) | 2022-04-20 |
| KR102102535B1 (en) | 2020-04-21 |
| US20210322468A1 (en) | 2021-10-21 |
| WO2020022736A1 (en) | 2020-01-30 |
| CN112533870A (en) | 2021-03-19 |
| KR20200023655A (en) | 2020-03-06 |
| EP3828137A1 (en) | 2021-06-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Foresi et al. | Inflammatory markers in bronchoalveolar lavage and in bronchial biopsy in asthma during remission | |
| CN110257297B (en) | Separated lactobacillus paracasei PC-01 for promoting oral health and application thereof | |
| WO2016184427A1 (en) | Low-oxygen-treated mesenchymal stem cell and use thereof | |
| CN113599506A (en) | Platinum nanoenzyme/glucose oxidase @ hyaluronic acid composite antibacterial material and preparation and application thereof | |
| CN109276711B (en) | Application of manganese type high-stability superoxide dismutase in improving autism and product | |
| CN111467472A (en) | Immunoregulation microsphere preparation targeting tumor-associated macrophages and preparation method and application thereof | |
| JP2022507837A (en) | Radiation protection nanoparticles | |
| Wright et al. | Perianal infection with beta haemolytic streptococcus. | |
| Huang et al. | Nano-platelets as an oxygen regulator for augmenting starvation therapy against hypoxic tumor | |
| CN112725232B (en) | Culture medium and method for culturing spirulina with high phycocyanin content | |
| Danes et al. | The Gardner syndrome: a cell culture study on kindred 109. | |
| US20210402004A1 (en) | Nanoparticle structure and method of forming the same | |
| EP1881838B1 (en) | Antitumor agent on the base of bcg vaccine, method for its preparation and its use | |
| CN112386708A (en) | Preparation of human serum albumin modified manganous-manganic oxide quantum dot and application of quantum dot in treatment of ischemic stroke | |
| Zhang et al. | Defect engineering endows NiTi stents with photothermal-enhanced catalytic activity for high-efficiency tumor therapy | |
| KR101782622B1 (en) | Ceria nanoparticle for biomedical treatment and pharmaceutical composition including the ceria nanocomposite | |
| JP7386458B2 (en) | Composition for treating colitis | |
| CN117653606B (en) | Mesenchymal stem cell exosome freeze-drying protective agent and application thereof | |
| Scarpa et al. | Establishment and characterization of a human neuroblastoma cell line | |
| CN117443410B (en) | ROS scavenging biocatalysis material and preparation and application thereof | |
| WO2022151334A1 (en) | Method for increasing infiltration of immune cells in tumor by means of high-pressure oxygen | |
| CN116550324A (en) | Iron single-atom catalyst and preparation method and application thereof | |
| KR102390674B1 (en) | Vaccine Composition for Preventing Canine Adenovirus Type 2 Infection | |
| CN110218765B (en) | Method for inhibiting growth of escherichia coli in anaerobic environment | |
| Sun et al. | Erythrocyte‐Derived Bioactive Nanovesicles Reverse the Immunosuppressive Function of Adenosine for Tumor Photoimmunotherapy |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20210126 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20220210 |
|
| A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20220909 |